Eiichi Ishii

Improved outcome in the treatment of pediatric multifocal Langerhans cell histiocytosis: Results from the Japan Langerhans Cell Histiocytosis Study Group-96 protocol study.

The treatment outcome of multifocal childhood Langerhans cell histiocytosis (LCH) has not been satisfactory and has resulted in poor therapeutic responses with high mortality and a high incidence of reactivation with late sequelae. To overcome these issues, the Japan LCH Study Group‐96 (JLSG‐96) protocol was conducted prospectively from 1996 to 2001 in Japan.

Correlation between phenotypic heterogeneity and gene mutational characteristics in familial hemophagocytic lymphohistiocytosis (FHL)

Classification of familial hemophagocytic lymphohistiocytosis (FHL) into FHL2, FHL3, and other subtypes based on genetic abnormalities has recently become possible. We studied the phenotypic differences among these subtypes in Japan.

Identification of novel MUNC13-4 mutations in familial haemophagocytic lymphohistiocytosis and functional analysis of MUNC13-4-deficient cytotoxic T lymphocytes.

Background: Familial haemophagocytic lymphohistiocytosis (FHL) has an autosomal recessive mode of inheritance and consists of at least three subtypes. FHL2 subtype with perforin (PRF1) mutation accounts for 30% of all FHL cases, while FHL with MUNC13-4 mutation was recently identified and designated as FHL3 subtype. Objective: To examine MUNC13-4 mutations and the cytotoxic function of MUNC13-4 deficient T lymphocytes in Japanese FHL patients Methods: Mutations of MUNC13-4 and the cytotoxicity of MUNC13-4-deficient cytotoxic T lymphocytes (CTL) were analysed in 16 Japanese families with non-FHL2 subtype. Results: Five new mutations of the MUNC13-4 gene were identified in six families. The mutations were in the introns 4, 9, and 18, and exons 8 and 19. Two families had homozygous mutations, while the remaining four had compound heterozygous mutations. Cytotoxicity of MUNC13-4 deficient CTL was low compared with control CTL, but was still present. Clinically, the onset of disease tended to occur late; moreover, natural killer cell activity was not deficient in some FHL3 patients. Conclusions:MUNC13-4 mutations play a role in the development of FHL3 through a defective cytotoxic pathway.

Occurrence of haemophagocytic lymphohistiocytosis at less than 1 year of age: analysis of 96 patients

We analysed data of 96 infants (under 1 year of age) with haemophagocytic lymphohistiocytosis (HLH) from the registry of an HLH study conducted during 1986–2002 in Japan. The cases were classified into five groups. The diagnosis of familial HLH (FHL) as group 1 (n =27) was made with positive family history and/or recent molecular test for perforin and Munc13–4 mutations. Neonatal enterovirus- or herpes simplex virus-associated HLH as group 2a (n =7), Epstein-Barr virus–associated HLH (n =12) as group 2b, adenovirus- or cytomegalovirus-associated HLH as group 3 (n =9) were mostly diagnosed by viral isolation or by the detection of viral genome. Juvenile rheumatoid arthritis-associated macrophage activation syndrome was classified as group 4 (n =4) and the remaining without known triggers as group 5 (n =37). The peak onset age was 1–2 months for group 1, 1–2 weeks for group 2a, 12 months for group 2b, none for group 3, 9 months for group 4 and 2 months for group 5. Future novel diagnostic measures are required to define the precise nature of HLH in group 5. Conclusion:These data may provide useful information for neonatologists/ paediatricians in the differential diagnosis of haemophagocytic lymphohistiocytosis in early infancy.

Mutations of syntaxin 11 and SNAP23 genes as causes of familial hemophagocytic lymphohistiocytosis were not found in Japanese people

AbstractAlthough mutations of perforin, MUNC13-4 and syntaxin 11 genes have been found in children with familial hemophagocytic lymphohistiocytosis (FHL), the incidence of each genetic subtype varies in different ethnic groups. We evaluated mutations of syntaxin 11 and SNAP23 genes in 30 Japanese FHL patients. The patients had no mutations and 10% had one polymorphism (146G>A) of syntaxin 11, while no mutation of SNAP23 was observed. Our results indicate that aberrations in the SNARE system may not cause FHL in Japanese families.

Common gene expression signatures in t(8;21)- and inv(16)-acute myeloid leukaemia

Human acute myeloid leukaemia (AML) involving a core‐binding factor (CBF) transcription factor is called CBF leukaemia. In these leukaemias, AML1 (RUNX1, PEBP2αB, CBFα2)‐MTG8 (ETO) and CBFβ (PEBP2β)‐MYH11 chimaeric proteins are generated by t(8;21) and inv(16) respectively. We analysed gene expression profiles of leukaemic cells by microarray, and selected genes whose expression appeared to be modulated in association with t(8;21) and inv(16). In a pair‐wise comparison, 15% of t(8;21)‐associated transcripts exhibited high or low expression in inv(16)‐AML, and 26% of inv(16)‐associated transcripts did so equivalently in t(8;21)‐AML. These common elements in gene expression profiles between t(8;21)‐ and inv(16)‐AML probably reflect the situation that AML1‐MTG8 and CBFβ‐MYH11 chimaeric proteins affect a common set of target genes in CBF leukaemic cells. On the other hand, 38% of t(8;21)‐associated and 24% of inv(16)‐associated transcripts were regulated in t(8;21)‐ and inv(16)‐specific manners. These distinct features of t(8;21)‐ and inv(16)‐associated genes correlate with the bimodular structures of the chimaeric proteins (CBF‐related AML1 and CBFβ portions, and CBF‐unrelated MTG8 and MYH11 portions).

Successful bone marrow transplantation in a patient with c‐mpl‐mutated congenital amegakaryocytic thrombocytopenia from a carrier donor

Abstract:u2002 Congenital amegakaryocytic thrombocytopenia (CAMT) is characterized by severe thrombocytopenia and the absence of megakaryocytes in bone marrow. Furthermore, mutation of the c‐mpl gene has been identified as a cause of this disorder. The only curative treatment is allogeneic stem cell transplantation (SCT). The current report describes a patient exhibiting c‐mpl mutation in both alleles who underwent transplantation of allogeneic bone marrow donated by her brother, a c‐mpl mutated carrier, employing a fludarabine‐based conditioning regimen. Engraftment and reconstitution of hematopoietic cells was rapid and without complications. These findings suggest that the carrier donor displaying the c‐mpl mutation can serve as a donor source for SCT.

Features and outcome of neonatal leukemia in Japan: Experience of the Japan Infant Leukemia Study Group

Neonatal leukemia characterized by early stem cell origin and extramedullary infiltration in the first 4 weeks of life is rare. We analyzed the features and outcome of neonatal leukemia in Japan to establish an appropriate treatment strategy for this rare disorder.

Expression and production of aberrant PAX5 with deletion of exon 8 in B-lineage acute lymphoblastic leukaemia of children

We investigated PAX5 expression in childhood B‐lineage acute lymphoblastic leukaemia (ALL). Seven of 21 children with B‐lineage ALL had multiple PAX5 variants, while 14 children and healthy controls showed full‐length (FL) and one variant PAX5. By Western blotting, healthy controls displayed Pax5‐FL, while one short Pax5, derived from the deletion of exon 8 (Pax5‐ΔE8) was produced in 90% of ALL samples, as well as in ALL cell lines. PAX5‐ΔE8 lacked more than 50% of the transactivation domain, indicating that aberrant Pax5 production might lead to the arrest of B‐cell differentiation, contributing to the pathogenesis of B‐lineage ALL.

Protein-losing gastroenteropathy and retinitis associated with cytomegalovirus infection in an immunocompetent infant: a case report

A 6-week-old immunocompetent girl developed protein-losing gastroenteropathy (PLGE) and retinitis associated with cytomegalovirus (CMV) infection. At presentation, CMV antigenaemia (6 cells/46,000 white blood cells) and its DNA were detected in the patient’s blood and in the mother’s milk. Intravenous ganciclovir and γ-globulin rapidly ameliorated all symptoms and CMV antigenaemia disappeared. No immunological defects were identified in this patient. To the best of our knowledge, this case involves the youngest known immunocompetent patient demonstrating CMV-induced PLGE and retinitis. Conclusion:breast-feeding by a cytomegalovirus-positive mother can be a primary cause of early onset cytomegalovirus infection in infants.